JPS5813586A - Reserpilinium quaternary salt derivative and antiarrhythmics - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(n is 1, 2; X is halogen; R1 is H, lower alkyl; R2 is lower alkyl which may be substituted with tri-lower-alkylamino ammonium; R3 is lower alkyl where the sum of the carbon number of the lower alkyl or R2 which may be substituted and that of the lower alkyl of R3 is at least 3). EXAMPLE:1-Methyl-4-n-propylreserpilinium iodide. USE:Antiarrhythmics PREPARATION:An equimolar or excessive amount of lower alkyl halide is added to a reserpiline derivative of formula II (R4 is H, lower alkyl; R5 is lower alkyl which may be substituted with di-lower alkylamino in a solvent such as nitromethane or dimethylsulfoxide and they are heated in a nitrogen atmosphere at 60-90 deg.C for 5-60hr so give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel reservinium quaternary salt derivatives and antiarrhythmic agents containing the same.

The reservinium quaternary salt derivative of this lI@ has the following 〇-Kin formula (in the formula, nr1119+120 integer, x%@7%
E! l) represents an atom, R1 represents a hydrogen atom, 11 represents a lower alkyl group, and %R2 represents a tri-lower alkyl amonoa.
1 is substituted with 4 equim groups, and R1 is a lower alkyl group, and R1 is a lower alkyl group.

S-, Rj optionally substituted lower alkyl group o*
It is expressed by the lower alkyl group (O prime number and 01a are at least 4s or more).

Resel N9 represented by the above general formula [I] of induced-
Rimuq! Quaternary salt derivatives are metal compounds useful as antiarrhythmic agents. Conventionally, the compound of RenOs is 14-methylrece kg 9 !, which is represented by the formula: Ram attack is known (J, Mm, Oh@m, 8oo,
J Volume aS Page 2507 (19!!ri and j*tot
・Refer to "Uchiben" Vol. 4S, page 67 (197B)), from Shikashi'&, this chemical compound - whether it has antiarrhythmic action or not. There are no reports.

As a result of various studies, these authors succeeded in obtaining novel quaternary salts of reservirinium, and surprisingly discovered that they have antiarrhythmic effects.

The induced W14 4IAh reservi 9=um quaternary salt derivative has the general formula (wherein R4 represents a hydrogen atom or a lower alkyl group, and l
l is substituted with di-lower alkyla) group and %X%A
(representing a lower alkyl group) for example, ethotetramethane.

Limethylsul is the preferred choice for the polarity of dimethylformia ζV, etc., and lower alkyl halides.
Add in an amount of lI4 l to a large excess and boil in a nitrogen stream for 40~
A method for isolating and purifying the target substance from the reaction solution is, for example, by reacting it under heating at 90 degrees Celsius for 5 to 60 hours. Add a non-polar solvent.

The synthesized quaternary salt of the present invention is precipitated, and the solvent and precipitate are separated by decantation.

The obtained precipitate is again dissolved in a small amount of methanol, ethanol, methane, dimethyl sulfoxy, dimethyl formamide, or other relatively polar solvent, and then again dissolved in a relatively polar solvent such as ether or benzene. is added to precipitate the quaternary salt. F° 4th separated by another force
It is possible to purify the salt by recrystallizing it with a solvent such as acetone.

The Omho assay of the reservirinium II quaternary salt derivative of the present invention was carried out to determine whether it inhibits the arrhythmia induced by adrenaline injection to the base of Lemotte. After intraperitoneally injecting 4 (Dfy lane) on 121/12, the animal is fixed in the dorsal position and placed in a quiet position in the external area.KOG electrodes are placed on the extremities and the electrocardiogram is observed in the second lead. After ~60 minutes of anesthesia, adrenaline is rapidly injected through the crab tube, and the amount of adrenaline is determined so that the resulting arrhythmia will last for 25 seconds to 60 minutes.The amount of epinephrine to be injected is set and tested after ~60 minutes. Gradually inject the metal intravenously. 5 minutes, 10 minutes, and 15 minutes after the intravenous injection of the test compound, SO + 11 Kb is also caulked, and the set amount of adrenaline is rapidly injected. 4.5 minutes later, 10 minutes 11 .15 minutes later, O adrenaline 7II Arrhythmia can be prevented by completing the meal more than once, and the amount of the 90% test compound can be inhibited by the minimum effective dose (LED).
), the Il constant result is as follows.

Effect on adrenaline arrhythmia Pukai/iV 80 S15 9
4.41.1・-Mei V Rujiso-〆ide The above O test compound is expressed by the general formula (IF and O Kaiun) as follows.

Test compound RI R2R111X U□ □ -1111 pyriecum 11〆idodide 1-methyl-4-n-pro methyl methyl
Propyl 11-biru-rekiruhiriri-otsumu-bendai-dite-1k (LD5G) was prepared by injecting the test compound dissolved in solvent K11l into the tail of a male male with a body weight of 20 to 2519. Litchfield Wilcoxono (
LitchfLe14-Wilcox On) method
Ew was determined 9th, and from the previous go Yoshika to Motoya, the new 9A'&
It can be seen that the reservinium quaternary salt derivative is a compound that has antiarrhythmic effects that are superior to known O compounds.

Synthesis example 1 1-Methyl-4-n-proviral ru♂ linium sterilization V methylreserpicy 61t nitromain 1s store Ki
12ml of n-propyl iodide was added and the mixture was heated under nitrogen for 80°C.
After cooling the reactant, which was allowed to react overnight at ℃, 40 m of ether was added at a time while stirring, and the precipitated powdery precipitate was filtered and recrystallized from ethanol. Yield 60
1(-!L891&).

IR: 1710.1650, 110 mouths χ1 (aromatic 21() !L4 (-0000H!51) 1@(
-oauB 4K) α@5 ()kl-(112
(li20jiB sg) Town fee: 22&0~22 melon・
°C Elemental analysis value: 011 III II Calculated value: 5 & 40 Table 04 482 adjustment value = 55s
7 Book s8 472 Adjustment Confucianism 2 4-! l-Zovirulecervirinium 22 (limenaru n-froVruane 4nium)-ethyl ester disodium-
〆id 118I (a027-t-ru) 02-CQIfa-7
1)-enalresel gelrine) t40slO Nitome#yK is dissolved, and the iodized n-pW gel of 30- is dissolved and heated under nitrogen at 80 DEG C. for 17 hours.

After cooling, the mixture was diluted with 1st 1- ether to remove the solvent.

Add a small amount of 07'tanol to the mixture, stir, and add 100 dO ether. The powder produced. Yield 19g (yield 8 & 2-) @ 11:5200, 1a 20.1420, 1110MMR
: 1 (L? 5 (6) &8 (-0013
11sH) m, p,: 19! Ls - 1911℃ According to each of the above-mentioned rules, the following O-chemicals should be recited.

4-n-i vx Hirurecell v9nium ■-Made IR: 5400. 1720.1440. 11001
1MR: 1 to (141)! L75
(-00Hi 411) & 9S (fragrance m, ""2u)
A 85 ()m-@42a4 in)・'1゜m, p, : 19 &7~1917℃1-Methyl-4-impupilureselzeIJLumseal-daiV EngineeringR;1700.1620.1100 7 .15 (aromatic 2m) 345 (-oooomg
! ! i) m, p,: 1741-17z8°C 4-methyl-recel 11! Linium 2-(trimethylamine)-ethyl ester distal-end XR125
G, 1720.14! ! 0.111011MR: 1
t2 (IHI) 18 (-001196M
) & 95 (aromatic 21) 52 (-N(011!I
)l 91) Theory, p, :1? ! 7～199.7℃ Elemental analysis value: (IIIHll I

Claims (1)

[Claims] 1) General formula (in the formula, 1 is 11 & e is 2t)
% R2 represents a lower alkyl group optionally substituted with a tri-lower tykylaminoane group, and R1 represents a hydrogen atom or a lower atom group; The sum of the number of carbon atoms of the group O in the lower alkyl which may be substituted (excluding the optionally present substituted moiety) and the number of carbon atoms of the Rst)'flk class alkyl group is at least S or more. ) is ahed and seven Ruzeriecum quaternary salt induced starvation. 2) General formula (in the formula, n represents an integer of 2, !-1tway atom, %R1 represents a hydrogen atom, 9 represents a lower alkyl group, R1 represents a tri-lower alkyl aminoamine group) represents a lower alkyl group optionally substituted with
represents lower alkyl a, Rj4D optionally substituted lower alkyl group O carbon number (excluding optional substituent group i), lower alkyl ka carbon number and Os are at least 3 An antiarrhythmic agent containing a reservirinium quaternary salt trout conductor represented by (1).